Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels

Pil Lee Kyu, Joseph P. Yuan, Weizhong Zeng, Insuk So, Paul F. Worley, Shmuel Muallem

Research output: Contribution to journalArticle

109 Scopus citations

Abstract

Ca2+ influx by store-operated Ca2+ influx channels (SOCs) mediates many cellular functions regulated by Ca2+, and excessive SOCmediated Ca2+ influx is cytotoxic and associated with disease. One form of SOC is the CRAC current that is mediated by Orai channels activated by STIM1. A fundamental property of the native CRAC and of the Orais is fast Ca2+-dependent inactivation, which limits Ca2+ influx to guard against cellular damage. The molecular mechanism of this essential regulatory mechanism is unknown. We report here the fast Ca 2+-dependent inactivation is mediated by three conserved glutamates in the C termini (CT) of Orai2 and Orai3, which show prominent fast Ca 2+-dependent inactivation compared with Orai1. Transfer of the CT between the Orais transfers both the extent of channel opening and the mode of fast Ca2+-dependent inactivation. Fast Ca2+-dependent inactivation of the Orais also requires a domain of STIM1; fragments of STIM1 that efficiently open Orai channels do not evoke fast inactivation unless they include an anionic sequence that is C-terminal to the STIM1-Orai activating region (SOAR). Our studies suggest that Orai CT are necessary and sufficient to control pore opening and uncover the molecular mechanism of fast Ca 2+-dependent inactivation that has implications for Ca2+ influx by SOC in physiological and pathological states.

Original languageEnglish
Pages (from-to)14687-14692
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number34
DOIs
StatePublished - 25 Aug 2009

Keywords

  • Calcium
  • Fast inactivation
  • STIM1

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